The M-CSF (macrophage colony stimulating factor) receptor, Fms, regulates the growth and development of the monocyte-macrophage lineage of blood cells. The structure of Fms is shared by several other tyrosine kinase growth factor receptors (e.g., the PDGF receptors, Kit, Flt3, and the FGF group of receptors) that transduce similar signals in distinct cells and tissues. In humans, mutations of some of these receptors result in disease states of the blood or tissues in which they are expressed, and our goal is to understand the diverse molecular mechanisms of signaling by this class of receptors using Fms as a paradigm. Recently we identified a new type of signal transduction protein designated SHIP for its structure (SH2-containing) and enzymatic function Inositol 5- Phosphatase activity). SHIP is expressed in most cells of the blood and tyrosine phosphorylated by multiple cytokines and their receptors, and surprisingly, exhibits negative growth regulation. Homologs of SHIP probably exist in most, if not all cells and tissues of eukaryotes. Therefore, SHIP has the potential to suppress or modulate positive growth factor receptor signaling and its relevance to the growth and differentiation signals regulated by Fms would be helpful to understand its role in normal growth and potential abnormalities in cancer. The focus of the proposed studies will be on biochemical studies of the signal transduction mechanism involving SHIP, production of transgenic and knockout mice for the investigation of the functional role of SHIP isoforms in individual blood cell lineages, and characterization of the genomic and spliced isoforms of SHIP to determine their role in normal blood cell development and contribution to leukemia development.